The invention relates to substituted 2-dialkylaminoalkylbiphenyl derivatives, processes for their preparation, medicaments comprising these compounds and the use of these compounds for the preparation of medicaments and methods of treatment using these components.
The treatment of chronic and non-chronic states of pain is of great importance in medicine. There is a worldwide demand for pain treatments which have a good efficacy. The urgent need for action in respect of patient-relevant and target-orientated treatment of chronic and non-chronic states of pain, this being understood as meaning successful and satisfactory pain treatment for the patient, is documented in the large number of scientific works which have recently appeared in the field of applied analgesia and fundamental research into nociception.
Conventional opioids, such as morphine, have a good action in the treatment of severe to very severe pain. However, their use is limited due to the known side effects, e.g. respiratory depressions, vomiting, sedation, constipation, addiction, dependency and development of tolerance. They can therefore be administered over a relatively long period of time or in relatively high dosages only with particular safety precautions, such as specific prescription instructions (Goodman, Gilman, The Pharmacological Basis of Therapeutics, Pergamon Press, New York 1990). Furthermore, they have a relatively low efficacy for some states of pain, in particular neuropathic pain.
An object of the instant invention was to provide analgesically active substances which are suitable for treatment of pain. Furthermore, these substances should have as few as possible of the side effects of opioid analgesics, such as nausea, vomiting, dependency, respiratory depression or constipation. Further objects are to provide active compounds for treatment of inflammatory and allergic reactions, depressions, drug and/or alcohol abuse, gastritis, diarrhoea, urinary incontinence, cardiovascular diseases, respiratory tract diseases, coughing, mental illnesses and/or epilepsy.
According to the invention, this is achieved by provision of new substituted 2-dialkylaminoalkylbiphenyl derivatives which are suitable for treatment of inflammatory and allergic reactions, depressions, drug and/or alcohol abuse, gastritis, diarrhoea, urinary incontinence, cardiovascular diseases, respiratory tract diseases, coughing, mental illnesses and/or epilepsy and which moreover have a pronounced analgesic action.
The invention therefore provides substituted 2-dialkylaminoalkylbiphenyl derivatives of the general formula I 
Wherein
n is 1 or 2,
the radicals R1, R2, R3, which are identical or different, represent H, F, Cl, Br, CN, NO2, CHO, SO2CH3, SO2CF3, OR6, NR6R7, a C1-6-alkyl, preferably a C1-3-alkyl, an aryl, an acetyl, an acetamidyl or a benzoyl radical, or represent an aryl radical bonded via a C1-6-alkylene group, preferably an aryl radical bonded via a C1-3-alkylene group;
or R1 and R2 together in each case denote the group OCH2O, OCH2CH2O , CHxe2x95x90CHO, CHxe2x95x90C(CH3)O or CHxe2x95x90CHNH;
the radicals R4, R5, which are identical or different, represent H, or represent a C1-6-alkyl radical, preferably a C1-3-alkyl radical;
the radicals R6, R7, which are identical or different, represent H, a C1-6-alkyl, preferably a C1-3-alkyl, or an aryl radical, or represent an aryl radical bonded via a C1-6-alkylene group, preferably an aryl radical bonded via a C1-3-alkylene group,
in the form of their bases and/or salts of physiologically tolerated acids.
However, the compounds
2xe2x80x2-dimethylaminomethylbiphenyl-2-carbaldehyde;
biphenyl-2-ylmethyldimethylamine;
2xe2x80x2-dimethylaminomethylbiphenyl-2-ol, and the corresponding hydrochloride;
(2xe2x80x2,3xe2x80x2-dimethoxybiphenyl-2-ylmethyl)dimethylamine, and the corresponding hydrochloride and the corresponding hydrobromide;
(4xe2x80x2-methylbiphenyl-2-ylmethyl)-dimethylamine;
(2xe2x80x2-methylbiphenyl-2-ylmethyl)-dimethylamine;
4-chloro-2xe2x80x2-dimethylaminomethylbiphenyl-2-carbonitrile;
(2xe2x80x2-dimethylaminomethylbiphenyl-2-yl)methanol;
2xe2x80x2-dimethylaminomethylbiphenyl-2,3-diol, and the corresponding hydrobromide;
[2-(3xe2x80x2,4xe2x80x2-dimethoxybiphenyl-2-yl)ethyl)]-dimethylamine, and the corresponding hydrochloride;
[2-(2xe2x80x2,3xe2x80x2-dimethoxy-6xe2x80x2-methylbiphenyl-2-yl)ethyl)]-dimethylamine, and the corresponding hydrobromide; and
biphenyl-2-ylethyldimethylamine are excluded.
Alkyl radicals are understood as meaning hydrocarbons which may be substituted, preferably by halogen and/or a hydroxyl group, particularly preferably by fluorine and/or a hydroxyl group. If there are more than one substituent, the substituents can be identical or different. The alkyl radicals methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, CHF2, CF3 or CH2OH are preferred.
An aryl radical is understood as meaning phenyls or naphthyl radicals which may be substituted by an OH, a halogen, preferably F and/or Cl, a CF3, a C1-6-alkyl, a C1-6-alkoxy, a C1-7-cycloalkoxy, a C3-7-cycloalkyl, a C2-6-alkylene or a phenyl radical. The phenyl radicals can also be condensed with further rings.
The following substituted 2-dimethylaminoalkylbiphenyl derivatives are particularly preferred:
(3xe2x80x2-methoxybiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride;
(4xe2x80x2-chlorobiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride;
2xe2x80x2-dimethylaminomethylbiphenyl-3-ol and the corresponding hydrochloride;
(2xe2x80x2-methoxybiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride;
(3xe2x80x2-chlorobiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride;
(2xe2x80x2-fluorobiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride;
(3xe2x80x2-fluorobiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride;
(4xe2x80x2-fluorobiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride;
(3xe2x80x2-chloro-4xe2x80x2-fluorobiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride;
(3xe2x80x2-methoxybiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride;
dimethyl-[2-(2-methylbenzofuran-4-yl)benzyl]amine and the corresponding hydrochloride;
2xe2x80x2-dimethylaminomethylbiphenyl-2-carbaldehyde and the corresponding hydrochloride;
(3xe2x80x2-difluoromethylbiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride;
2xe2x80x2-dimethylaminomethylbiphenyl-3-carbaldehyde and the corresponding hydrochloride;
biphenyl-2-ylmethyldimethylamine and the corresponding hydrochloride;
(3xe2x80x2,4xe2x80x2-dichlorobiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride;
(3xe2x80x2,5xe2x80x2-dichlorobiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride;
dimethyl-(4xe2x80x2-nitro-3xe2x80x2-trifluoromethylbiphenyl-2-ylmethyl)-amine and the corresponding hydrochloride;
(3xe2x80x2,4xe2x80x2-difluorobiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride;
(4xe2x80x2-fluoro-3xe2x80x2-trifluoromethylbiphenyl-2-ylmethyl)dimethyl-amine and the corresponding hydrochloride;
(4xe2x80x2-chloro-3xe2x80x2-methoxybiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride;
N-(2xe2x80x2-dimethylaminomethyl-3-trifluoromethoxybiphenyl-4-yl)acetamide and the corresponding hydrochloride;
(3xe2x80x2-isopropoxybiphenyl-2-ylmethyl)dimethylamine and the corresponding and the corresponding hydrochloride;
2xe2x80x2-(2-dimethylaminoethyl)biphenyl-3-ol and the corresponding hydrochloride;
4-chloro-2xe2x80x2-dimethylaminomethylbiphenyl-3-ol and the corresponding hydrochloride;
[2-(1H-indol-5-yl)benzyl]dimethylamine and the corresponding hydrochloride;
(4xe2x80x2-methanesulfonylbiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride;
(2xe2x80x2,4xe2x80x2-dichlorobiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride;
(2xe2x80x2,3xe2x80x2-difluorobiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride;
(2xe2x80x2,5xe2x80x2-difluorobiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride;
(2-benzo [1,3]dioxol-5-ylbenzyl)dimethylamine and the corresponding hydrochloride;
1-[2xe2x80x2-(2-dimethylaminoethyl)biphenyl-3-yl]ethanone and the corresponding hydrochloride;
[2-(3xe2x80x2,4xe2x80x2-dimethoxybiphenyl-2-yl)ethyl]dimethylamine and the corresponding hydrochloride;
[2-(3xe2x80x2-isopropoxybiphenyl-2-yl)ethyl]dimethylamine and the corresponding hydrochloride;
[2-(4xe2x80x2-chloro-3xe2x80x2-methoxybiphenyl-2-yl) ethyl]dimethylamine and the corresponding hydrochloride;
4-chloro-2xe2x80x2-(2-dimethylaminoethyl)biphenyl-3-ol and the corresponding hydrochloride;
dimethyl-(3xe2x80x2-nitrobiphenyl-2-ylmethyl)amine and the corresponding hydrochloride;
4-amino-2xe2x80x2-dimethylaminomethylbiphenyl-3-ol and the corresponding dihydrochloride;
(3xe2x80x2,5xe2x80x2-difluorobiphenyl-2-ylmethyl) dimethylamine and the corresponding hydrochloride;
(2xe2x80x2,5xe2x80x2-dimethoxybiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride;
2xe2x80x2-dimethylaminomethyl-5-trifluoromethoxybiphenyl-2-ylamine and the corresponding dihydrochloride;
N-(2xe2x80x2-dimethylaminomethyl-5-trifluoromethoxybiphenyl-2-yl)acetamide and the corresponding hydrochloride; and
3,5-dichloro-2xe2x80x2-dimethylaminomethyl-biphenyl-4-ylamine and the corresponding hydrochloride.
The invention also provides processes for the preparation of substituted 2-dialkylaminoalkylbiphenyl derivatives of the general formula I. The processes are characterized in that the compounds of the general formula II, wherein Y denotes Cl, Br or I and m denotes 0 or 1, 
are reduced in solution with a reducing agent, preferably lithium aluminium hydride and/or diisobutylaluminium hydride, to give rise to compounds of the general formula III, wherein n denotes 1 or 2, 
and these are purified and isolated by conventional methods.
The compounds of the general formula III are then reacted with aliphatic C1-6-aldehydes in the presence of a reducing agent, preferably formic acid and/or sodium borohydride, to give rise to compounds of the general formula IV 
wherein R4 and R5 have the meaning according to the general formula I, and these are purified and isolated by conventional methods.
The compounds of the general formula IV are further converted by halogen-metal exchange, preferably with magnesium and/or butyllithium, and subsequent reaction with a boric acid ester, preferably a trialkyl borate, particularly preferably with a trimethyl borate, at temperatures of xe2x89xa60xc2x0 C. to give rise to compounds of the general formula V, 
wherein R denotes a C1-6-alkyl radical, and these are isolated and purified by conventional methods.
The compounds of the general formula V can be reacted with aqueous acids, preferably hydrochloric acid, to give rise to compounds of the general formula VI 
and these can be purified and isolated by conventional methods.
The compounds of the general formula V or VI are reacted in a transition metal-catalysed reaction, preferably in a reaction catalysed by palladium(0) compounds or by palladium(II) salts, particularly preferably by tetrakis(triphenylphosphine)palladium, bis(dibenzylideneacetone)palladium, elemental palladium on active charcoal, palladium(II) chloride and/or palladium(II) acetate, in an aliphatic ether, preferably 1,4-dioxane and tetrahydrofuran, or a hydrocarbon, preferably toluene or hexane, an alcohol, preferably ethanol or isopropanol, a chlorinated hydrocarbon, preferably chloroform or methylene chloride, in water or mixtures of these solvents at temperatures between 20 and 150xc2x0 C. with compounds of the general formula VII 
wherein X denotes Cl, Br, I or OSO2CpF(2p+1) and the radicals R1 to R3 have the meaning according to the general formula I, to give rise to compounds of the general formula I and these are purified and isolated by conventional methods.
Alternatively, the compounds of the general formula VIII or IX 
wherein R1 to R3 have the meaning according to the general formula I, are reacted in a transition metal-catalysed reaction, preferably in a reaction catalysed by palladium(0) compounds or by palladium(II) salts, particularly preferably by tetrakis(triphenylphosphine)palladium, bis(dibenzylideneacetone)palladium, elemental palladium on active charcoal, palladium(II) chloride and/or palladium(II) acetate, in an aliphatic ether, preferably 1,4-dioxane and tetrahydrofuran, or a hydrocarbon, preferably toluene or hexane, an alcohol, preferably ethanol or isopropanol, a chlorinated hydrocarbon, preferably chloroform or methylene chloride, in water or mixtures of these solvents at temperatures between 20 and 150xc2x0 C. with compounds of the general formula III or IV to give rise to compounds of the general formula I and these are purified and isolated by conventional methods.
The compounds of the general formula I can be converted into their salts in the manner known to a skilled person in the art with physiologically tolerated acids, for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid. The salt formation is preferably carried out in a solvent, for example diethyl ether, diisopropyl ether, acetic acid alkyl esters, acetone and/or 2-butanone. Trimethylchlorosilane in aqueous solution is moreover suitable for preparation of the hydrochlorides.
The substituted 2-dialkylaminoalkylbiphenyl derivatives of the general formula I according to the invention are toxicologically acceptable and are therefore suitable pharmaceutical active compounds.
The invention therefore also provides medicaments or pharmaceutical compositions which comprise, as the active compound, at least one substituted 2-dialkylaminoalkylbiphenyl derivative of the general formula I in the form of its base and/or a salt of a physiologically tolerated acid and optionally further active compounds and auxiliary substances.
The medicaments are preferably employed for treatment or control of pain, inflammatory and allergic reactions, depressions, drug and alcohol abuse, gastritis, diarrhoea, urinary incontinence, cardiovascular diseases, respiratory tract diseases, coughing, mental illnesses and/or epilepsy.
The invention also additionally provides the use of at least one substituted 2-dialkylaminoalkylbiphenyl derivative of the general formula I in the form of its base and/or a salt of a physiologically tolerated acid for the preparation of a medicament and for treatment or control of pain, inflammatory and allergic reactions, depressions, drug and alcohol abuse, gastritis, diarrhoea, urinary incontinence, cardiovascular diseases, respiratory tract diseases, coughing, mental illnesses and/or epilepsy.
To prepare corresponding pharmaceutical formulations, in addition to at least one substituted 2-dimethylaminoalkylbiphenyl derivative of the general formula I, carrier materials, fillers, solvents, diluents, dyestuffs and/or binders are employed. The choice of auxiliary substances and the amounts thereof to be employed depend on whether the medicament is to be administered orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or locally, for example on infections on the skin, the mucous membranes and on the eyes. Formulations in the form of tablets, coated tablets, capsules, granules, drops, juices and syrups are suitable for oral administration, and solutions, suspensions, easily reconstitutable dry formulations and sprays are suitable for parenteral, topical and inhalatory administration. Compounds of the general formula I according to the invention in a depot, in dissolved form or in a patch, optionally with the addition of agents which promote penetration through the skin, are suitable percutaneous administration formulations. Formulation forms which can be used orally or percutaneously can release the compounds of the general formula I according to the invention in a retarded manner.
The amount of active compound to be administered to the patient varies according to the weight of the patient, the mode of administration, the indication and the severity of the illness. Usually 0.5 to 500 mg/kg of at least one 2-dialkylaminoalkylbiphenyl derivative of the general formula I are administered.